A genetic variant near the gene for MTHFD1L on chromosome 6 likely doubles a person’s risk of late-onset Alzheimer disease, according to research presented today at the American Academy of Neurology meeting in Toronto, Canada. The discovery, from a large genomewide association screen, jibes well with what is known about the protein’s role in metabolizing homocysteine, a known risk factor for Alzheimer’s. First author Adam Naj and principal investigator Margaret Pericak-Vance, both of the University of Miami, Florida, outlined the finding in a poster session.

The study authors hunted for AD-linked genes in a genomewide association study encompassing nearly 500,000 SNPs and including more than 2,000 AD subjects, and over 3,000 controls in the combined discovery and confirmation datasets. They found that SNPs in and around the MTHFD1L gene were linked to AD risk, with the disease-associated variants doubling risk. In comparison, the ApoE4 allele increases AD risk by a factor of 3.68. However, the presenters noted that the odds ratio of two is likely to go down a bit with further study.

MTHFD1L encodes a protein, methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like, that may help convert homocysteine into methionine, so problems with this gene might lead to elevated homocysteine levels. Increased plasma homocysteine is a well-known AD risk factor (see ARF related news story on Seshadri et al., 2002). In addition, MTHFD1L variants have been linked to coronary disease (Coronary Artery Disease Consortium, 2009) and dementia can be caused by reduced blood flow to the brain, so the link among MTHFD1L, Alzheimer’s, and coronary disease is compelling, Pericak-Vance said.

Other studies have not found a significant association between SNPs near MTHFD1L AD (see AlzGene), although some GWAS have come close. Pericak-Vance and Naj suggested that their study met stringent statistical GWAS thresholds because of the particular SNPs they analyzed, and the size of the cohort.

The authors speculated that carriers of the MTHFD1L disease-linked variant are unable to properly convert homocysteine to methionine, allowing homocysteine to build up. This molecule could then cause disease by altering vasculature, increasing oxidative stress, or poisoning cortical neurons. However, Naj noted that it is too soon to be sure what happens in people with different MTHFD1L variants. “We have no evidence to go on as to what it actually does,” he told ARF. As with any GWAS, it will be necessary to look for the significance of this gene in other datasets to confirm its importance. The researchers are currently sequencing MTHFD1L and testing plasma homocysteine levels in control and AD samples.—Amber Dance.

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  1. The enzyme MTHFD1L does not directly catalyze the conversion of homocysteine to methionine. Also, there is no current evidence that mutations in the gene for MTHFD1L cause elevated homocysteine levels. The finding that a variant of MTHFD1L is linked to the risk of AD is very interesting, but the mechanism of its effect is likely to be complex. MTHFD1L is the mitochondrial form of an enzyme whose function is to catalyze a reversible transformation of 5,10-methylenetetrahydrofolate to 10-formyl tetrahydrofolate (10-formylTHF). 10-formylTHF serves as a formyl donor for MET-tRNA in mitochondrial protein synthesis, and as a precursor of purines. 10-formylTHF may also be hydrolyzed to formate, which passes out of the mitochondria into the cytoplasm. In the cytoplasm formate enters the one-carbon pool through an ATP-dependent conversion to 10-formylTHF, catalyzed by the trifunctional enzyme MTHFD1—the cytoplasmic form of the enzyme (MacFarlane et al., 2009). So, the most that can be said about a variant of MTHFD1L is that it might well in some way interfere with normal one-carbon metabolism, in particular if folate status is compromised. There is much evidence that changes in one-carbon metabolism may be related to AD (Smith, 2008), but without further data we cannot yet directly link the new finding to homocysteine.

    References:

    . Mthfd1 is an essential gene in mice and alters biomarkers of impaired one-carbon metabolism. J Biol Chem. 2009 Jan 16;284(3):1533-9. PubMed.

    . The worldwide challenge of the dementias: a role for B vitamins and homocysteine?. Food Nutr Bull. 2008 Jun;29(2 Suppl):S143-72. PubMed.

References

News Citations

  1. Want to Keep Your DNA in Good Repair? Then Eat Your Spinach!

Paper Citations

  1. . Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002 Feb 14;346(7):476-83. PubMed.
  2. . Large scale association analysis of novel genetic loci for coronary artery disease. Arterioscler Thromb Vasc Biol. 2009 May;29(5):774-80. PubMed.

External Citations

  1. ApoE4
  2. AlzGene

Further Reading

Papers

  1. . A second locus for very-late-onset Alzheimer disease: a genome scan reveals linkage to 20p and epistasis between 20p and the amyloid precursor protein region. Am J Hum Genet. 2002 Jul;71(1):154-61. PubMed.
  2. . Association studies of 22 candidate SNPs with late-onset Alzheimer's disease. Am J Med Genet B Neuropsychiatr Genet. 2009 Jun 5;150B(4):520-6. PubMed.
  3. . Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol. 2008 Jan;65(1):45-53. PubMed.
  4. . Oxidative DNA damage and level of thiols as related to polymorphisms of MTHFR, MTR, MTHFD1 in Alzheimer's and Parkinson's diseases. Acta Neurobiol Exp (Wars). 2007;67(2):113-29. PubMed.
  5. . GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers. Neuron. 2007 Jun 7;54(5):713-20. PubMed.
  6. . Results of a high-resolution genome screen of 437 Alzheimer's disease families. Hum Mol Genet. 2003 Jan 1;12(1):23-32. PubMed.